[unreadable] [unreadable] Lung cancer is the most common lethal malignancy for men and women. With the absence of curative therapy for advanced stage lung cancer, chemoprevention is an appealing strategy to combat this major public health problem. This NIH R03 application responds to PAR-06-313: Small Grants in Cancer Chemoprevention and takes advantage of novel transgenic human cyclin E mouse models that we engineered to target expression in the lung with the human surfactant C (SP-C) promoter. Wild-type and proteasome-degradation resistant cyclin E lines were each engineered. Notably, these lines developed chromosome instability, pre-malignancy, single or multiple lung adenocarcinomas and even metastases. Unexpectedly, a common feature of these lines was activation of the hedgehog (Hh) pathway in pre-malignant and malignant lung lesions. These findings build on our prior published work that Hh pathway activation frequently occurs in non-small cell lung cancer. These unique resources and an extensive panel of lung cancer cell lines will be used to explore Hh pathway targeting in lung cancer chemoprevention using the antagonist cyclopamine. Two specific aims are: (1) to comprehensively explore growth suppressive effects of cyclopamine in human and murine immortalized and malignant lung epithelial cell lines (including those engineered with Hh pathway gain or loss function and novel lung cancer cell lines from transgenic cyclin E lung tumors) and (2) to extend studies to the in vivo setting by learning whether cyclopamine suppresses lung carcinogenesis in mice and even prevents transgenic cyclin E lines from developing pre-malignant or malignant lung lesions. These findings would provide a strong rationale to translate work into the clinic in the future. Given the major public health impact from successful conclusion of these aims, we are eager to pursue these studies. [unreadable] [unreadable] [unreadable]